On the Cusp of Full Approval, Leqembi’s Rollout Could Face Challenges

Alzheimers concept_iStock

Pictured: A physician studies a brain scan/iStock, sudok1 

Last week, an FDA advisory committee gave Eisai and Biogen’s Alzheimer’s drug Leqembi (lecanemab) its unanimous blessing for traditional approval, signaling it will likely become the first drug of its class to receive this classification. While this is positive news for the biopharma partners and Alzheimer’s patients, concerns linger about the drug’s safety and Medicare coverage.

While the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 6-0 in favor of full approval, the advisers did have questions about Leqembi’s safety in certain subgroups, committee member Merit Cudkowicz, chief of the neurology department at Massachusetts General Hospital, said in a statement after the vote. That said, she called the evidence for clinical benefit “very clear and very robust.”

FDA briefing documents released before Friday’s meeting noted amyloid-related imaging abnormalities (ARIA), cerebral hemorrhage and infusion-related reactions and hypersensitivity as the main safety signals associated with anti-amyloid antibodies. 

Brain swelling (ARIA-E) occurred in 13% of Leqembi-treated patients in the Phase III CLARITY AD trial. In comparison, 14% of Leqembi-treated patients experienced microhemorrhages (ARIA-H), according to the briefing documents. These incidences were at least 2% higher than in those who received the placebo, the regulator noted.

Discussion points focused on three groups of patients who seem to be at greater risk for ARIA: apolipoprotein E (ApoE) ε4 homozygotes—or people with two copies of the ApoE ε4 allele, a known genetic risk factor in the development of Alzheimer’s disease—as well as those requiring concomitant treatment with anticoagulant agents and people with cerebral amyloid angiopathy (CAA), a condition where amyloid proteins build up on arterial walls in the brain. 

Ultimately, the panel found the risk-to-benefit profile to be acceptable for these groups, with monitoring in the early months of treatment when ARIA tended to occur, according to Pharmaphorum.   

Paul Matteis_Stifel2
Paul Mattei

Paul Matteis, managing director and co-head of the Biotech Research Team at Stifel, told BioSpace that in the case of full approval, “we could see some incrementally firmer language around safety warnings in certain populations—concomitant anticoagulant use, CAA—but I don’t expect any new contraindications, and ultimately I don’t think this will impact things all that significantly.”

Based on Stifel’s conversations with physicians, Matteis said that some doctors are much more comfortable with [the] safety/ARIA risk, while others are more cautious. “I don’t think modest changes to labeling language, assuming we’re right, will likely sway these views.”  

John Dickson, a neurologist at Mass Gen and instructor in neurology at Harvard Medical School, told BioSpace that if Leqembi is fully approved, he would want to have “very clear conversations” with patients about its potential risks and benefits to help them make an informed treatment decision.

He added that the risks of monoclonal antibodies, which are given by infusion, are generally higher than those of past Alzheimer’s treatments such as pills and patches and require more intensive monitoring. “It definitely requires some careful consideration on the parts of the patients and the providers taking care of them to really weigh the risks and benefits of this medication.” 

John Dickson_Massachusetts General Hospital
John Dickson

Registry Reactions

On June 1, Medicare elaborated on its intentions to broaden coverage for Alzheimer’s drugs like Leqembi if they receive full FDA approval. Specifically, the Centers for Medicare & Medicaid Services (CMS) stated that it would provide coverage for anyone with Medicare Part B who meets the prescribing criteria.

CMS attached a caveat to this coverage; however: Prescribing physicians will be required to participate in a registry that will collect real-world evidence about how Leqembi works. Some industry and patient groups believe this will limit access.

Biopharma industry group PhRMA said in a statement that the registry would “severely restrict patient access to FDA-approved medicines, leaving in place barriers to potentially life-changing treatment options for a devastating illness,” according to Pharmaceutical Technology. The Alzheimer’s Association, meanwhile, said in a statement that registries as a condition of coverage are an “unnecessary barrier.”

Matteis said that this approach, sometimes called coverage with evidence development (CED), is more often a tool leveraged for medical devices that launch with less clinical evidence. 

“This is why the CED for lecanemab, given the positive Phase III data in a large, randomized trial, is unprecedented and has elicited a negative reaction from some physicians and patient groups,” he said. “But in practice for lecanemab, it probably further slows early uptake.” 

In its June 1 announcement, CMS compared the proposed registry for Leqembi to the one required under the traditional FDA approval of transcatheter aortic valve replacement (TAVR). Physicians had to pay to enroll in this registry program and fill out a detailed, 11-page data collection form for each patient, Matteis said.

“For lecanemab, we don’t know exactly what may be required, but the assessment and reporting of outcomes on various cognitive metrics, along with safety data—ARIA, other adverse events—along with detailed patient demographic data, seems realistic,” he said.

Dickson said that if the registry involves extensive surveys and neuropsychological evaluation, completing a traditional clinical visit could be challenging. “So it’s important to make sure that whatever is included in a study of this type or a registry is practical within the confines of a routine clinical visit.”

Rob Smith_Capital Alpha Partners
Rob Smith

Rob Smith, managing director at Capital Alpha Partners, said that in the case of Leqembi, CED is a “pretty appropriate coverage pathway.”

“You have a drug that addresses a very large unmet medical need, that has tremendous financial implications for the Medicare program, and then it has some questionable clinical utility as well, so I think it’s certainly appropriate to have a very comprehensive measurement of how this drug works,” he told BioSpace.

Eisai has set the price of Leqembi at $26,500 per patient per year. According to the Kaiser Family Foundation, if 10% of the 6.7 million older adults with Alzheimer’s take Leqembi at this price, it would cost Medicare $17.8 billion—almost half of what Medicare Part B spent on all drugs in 2021.

Smith said the registry is intended to provide a follow-on for clinical data that can be compared against the trial results for anti-amyloid antibodies and that, depending on the results, it could lead to future label expansions for Leqembi.  

Leqembi won accelerated FDA approval in January. The FDA is expected to announce a decision on full approval on or before July 6. 

“You have to think that Leqembi is almost assured full approval at this point,” Smith said. 

Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.

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